JP5184783B2 - テトラヒドロビオプテリン、及びテトラヒドロビオプテリン類似体の製造方法 - Google Patents
テトラヒドロビオプテリン、及びテトラヒドロビオプテリン類似体の製造方法 Download PDFInfo
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- JP5184783B2 JP5184783B2 JP2006539994A JP2006539994A JP5184783B2 JP 5184783 B2 JP5184783 B2 JP 5184783B2 JP 2006539994 A JP2006539994 A JP 2006539994A JP 2006539994 A JP2006539994 A JP 2006539994A JP 5184783 B2 JP5184783 B2 JP 5184783B2
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- substituted
- acetal
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- alkyl
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- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 title claims description 50
- 229960004617 sapropterin Drugs 0.000 title claims description 41
- 238000004519 manufacturing process Methods 0.000 title description 7
- -1 t-butyldimethylsilyl group Chemical group 0.000 claims description 98
- 238000000034 method Methods 0.000 claims description 96
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 150000001875 compounds Chemical class 0.000 claims description 74
- 125000003277 amino group Chemical class 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 54
- BMQYVXCPAOLZOK-XINAWCOVSA-N neopterin Chemical compound OC[C@@H](O)[C@@H](O)C1=CN=C2NC(N)=NC(=O)C2=N1 BMQYVXCPAOLZOK-XINAWCOVSA-N 0.000 claims description 52
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 51
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 38
- 150000003568 thioethers Chemical class 0.000 claims description 32
- 230000009467 reduction Effects 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- BMQYVXCPAOLZOK-UHFFFAOYSA-N Trihydroxypropylpterisin Natural products OCC(O)C(O)C1=CN=C2NC(N)=NC(=O)C2=N1 BMQYVXCPAOLZOK-UHFFFAOYSA-N 0.000 claims description 26
- 150000001241 acetals Chemical class 0.000 claims description 23
- 125000006239 protecting group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 claims description 12
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000007868 Raney catalyst Substances 0.000 claims description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 6
- 230000009466 transformation Effects 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 5
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 5
- 150000003141 primary amines Chemical group 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical group CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004036 acetal group Chemical group 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 claims description 2
- MCIPQLOKVXSHTD-UHFFFAOYSA-N 3,3-diethoxyprop-1-ene Chemical compound CCOC(C=C)OCC MCIPQLOKVXSHTD-UHFFFAOYSA-N 0.000 claims description 2
- GSKVLVXXJRJNAN-UHFFFAOYSA-N [di(propan-2-yl)-$l^{3}-silanyl]oxy-di(propan-2-yl)silicon Chemical group CC(C)[Si](C(C)C)O[Si](C(C)C)C(C)C GSKVLVXXJRJNAN-UHFFFAOYSA-N 0.000 claims description 2
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 2
- 239000012965 benzophenone Substances 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 claims description 2
- PWAPCRSSMCLZHG-UHFFFAOYSA-N cyclopentylidene Chemical group [C]1CCCC1 PWAPCRSSMCLZHG-UHFFFAOYSA-N 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 150000003871 sulfonates Chemical class 0.000 claims 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 2
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims 2
- 125000005604 azodicarboxylate group Chemical group 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- HNXQXTQTPAJEJL-UHFFFAOYSA-N 2-aminopteridin-4-ol Chemical compound C1=CN=C2NC(N)=NC(=O)C2=N1 HNXQXTQTPAJEJL-UHFFFAOYSA-N 0.000 description 41
- 238000006722 reduction reaction Methods 0.000 description 27
- 125000004354 sulfur functional group Chemical class 0.000 description 23
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 238000010511 deprotection reaction Methods 0.000 description 14
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000006263 metalation reaction Methods 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 125000002252 acyl group Chemical group 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 239000004310 lactic acid Substances 0.000 description 9
- 235000014655 lactic acid Nutrition 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- LHQIJBMDNUYRAM-DZSWIPIPSA-N L-erythro-biopterin Chemical class N1=C(N)NC(=O)C2=NC([C@@H](O)[C@@H](O)C)=CN=C21 LHQIJBMDNUYRAM-DZSWIPIPSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- WDRISBUVHBMJEF-YUPRTTJUSA-N (2r,3s,4s)-2,3,4-trihydroxypentanal Chemical compound C[C@H](O)[C@H](O)[C@@H](O)C=O WDRISBUVHBMJEF-YUPRTTJUSA-N 0.000 description 6
- BOEUHAUGJSOEDZ-UHFFFAOYSA-N 2-amino-5,6,7,8-tetrahydro-1h-pteridin-4-one Chemical compound N1CCNC2=C1C(=O)N=C(N)N2 BOEUHAUGJSOEDZ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- LHQIJBMDNUYRAM-UHFFFAOYSA-N L-erythro-Biopterin Natural products N1=C(N)NC(=O)C2=NC(C(O)C(O)C)=CN=C21 LHQIJBMDNUYRAM-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical group COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical group COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 125000005594 diketone group Chemical group 0.000 description 3
- PSHRANCNVXNITH-UHFFFAOYSA-N dimethylamino acetate Chemical compound CN(C)OC(C)=O PSHRANCNVXNITH-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- RKSUYBCOVNCALL-NTVURLEBSA-N sapropterin dihydrochloride Chemical compound Cl.Cl.N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 RKSUYBCOVNCALL-NTVURLEBSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- UJFBUGYDKFCOBD-GARJFASQSA-N (2S,3R,4S)-5-(phenylhydrazinylidene)pentane-1,2,3,4-tetrol Chemical compound OC[C@H](O)[C@H](O)[C@@H](O)C=NNC1=CC=CC=C1 UJFBUGYDKFCOBD-GARJFASQSA-N 0.000 description 2
- 0 *CC1(CC1)[C@@](c(cn1)nc2c1N=C(*)NC2=O)O*O Chemical compound *CC1(CC1)[C@@](c(cn1)nc2c1N=C(*)NC2=O)O*O 0.000 description 2
- HUSXNIFVQFHSEA-UHFFFAOYSA-N 2-hydroxypropanoic acid;hydrochloride Chemical compound Cl.CC(O)C(O)=O HUSXNIFVQFHSEA-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 201000011252 Phenylketonuria Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 230000000035 biogenic effect Effects 0.000 description 2
- BUZRUIZTMOKRPB-UHFFFAOYSA-N carboxycarbamic acid Chemical compound OC(=O)NC(O)=O BUZRUIZTMOKRPB-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000002667 nucleating agent Substances 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- FNKQXYHWGSIFBK-UHFFFAOYSA-N (1'R,2'S,6R)-5,6,7,8-Tetrahydrobiopterin Natural products N1=C(N)NC(=O)C2=C1NCC(C(O)C(O)C)N2 FNKQXYHWGSIFBK-UHFFFAOYSA-N 0.000 description 1
- GUWCMUQEHMMXGW-SFHVURJKSA-N (2s)-2-trityloxypropan-1-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O[C@H](CO)C)C1=CC=CC=C1 GUWCMUQEHMMXGW-SFHVURJKSA-N 0.000 description 1
- JZBRSHYLBVFLLL-SFHVURJKSA-N (2s)-2-trityloxypropanal Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O[C@@H](C)C=O)C1=CC=CC=C1 JZBRSHYLBVFLLL-SFHVURJKSA-N 0.000 description 1
- 150000000180 1,2-diols Chemical group 0.000 description 1
- KXRRNQVFPBYRHD-UHFFFAOYSA-N 1,4,5-triamino-2h-pyrimidin-2-ol Chemical compound NN1C=C(N)C(N)=NC1O KXRRNQVFPBYRHD-UHFFFAOYSA-N 0.000 description 1
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- 239000007805 chemical reaction reactant Substances 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
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- 239000010941 cobalt Substances 0.000 description 1
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- 229910052802 copper Inorganic materials 0.000 description 1
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- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 238000003818 flash chromatography Methods 0.000 description 1
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- 125000002541 furyl group Chemical group 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
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- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
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- 150000002923 oximes Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052706 scandium Inorganic materials 0.000 description 1
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical group C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
N2−N,N−ジメチルアミノメチレン−L−ネオプテリン(R1がジメチルアミノメチレン−イミン基である、式6の化合物)の調製を、11.68gのL−ネオプテリン及び850mlの乾燥N,N−ジメチルホルムアミドを含むフラスコに、15.8mlのN,N−ジメチルホルムアミドジエチルアセタールを加えることによって調製した。全ての出発物質が溶解するまで、混合物を室温で撹拌した。室温で6時間撹拌した後、280mlの乾燥メタノールを加え、反応混合物及び混合物を、更に12時間撹拌した。全ての溶媒を蒸発させた後、反応混合物からの残渣を、500mlのジクロロメタンに懸濁し、次いで、懸濁した物質を集め、150mlのジクロロメタンで洗浄し、生じた生成物を40℃で減圧乾燥し、11.23gのN2−N,N−ジメチルアミノメチレン−L−ネオプテリンを得た。
第一級ヒドロキシル基の選択的保護を、実施例1で調製した、2−アミノ保護L−ネオプテリンを用いて行った。最初に、10gのN2−N,N−ジメチルアミノメチレン−L−ネオプテリンを、250mlの乾燥N,N−ジメチルホルムアミドに懸濁し、次いで、4.9gのイミダゾール及び10gのt−ブチルジフェニルクロロシランを反応混合物に加えることにより、N2−N,N−ジメチルアミノメチレン−3’O(t−ブチル−ジフェニルシリル)−L−ネオプテリンを調製した。反応混合物を室温で2時間撹拌した後、0.5gのイミダゾール及び1gのt−ブチルジフェニルクロロシランを加えた。反応混合物を室温で更に14時間撹拌した後、反応混合物を蒸発して乾燥し、残渣を、9:1〜6:4のジクロロメタン/メタノールの勾配を用いたシリカゲルによるフラッシュクロマトグラフィーにより精製した。生成物画分をプールして濃縮した。残渣を100mlのイソプロパノールい懸濁し、生成物を集め、イソプロパノールで洗浄し、40℃で減圧乾燥し、9.3gのN2−N,N−ジメチルアミノメチレン−3’(t−ブチル−ジフェニルシリル)−L−ネオプテリンを得た。
また、第一級ヒドロキシル基の選択的保護を、実施例1で調製した、2−アミノ保護L−ネオプテリンを用いて行い、選択的保護の後、2−アミノ基の脱保護を、同じフラスコ中で行い、3’O−(t−ブチル−ジフェニルシリル)−L−ネオプテリンを得た。
反応混合物を室温で14時間撹拌した後、反応混合物を濃縮して乾燥し、粗精製のN2−N,N−ジメチルアミノメチレン−3’(t−ブチル−ジフェニルシリル)−L−ネオプテリンを、160mlのエタノールに溶解した。エタノールに溶解することにより、15gの塩化亜鉛を反応フラスコに加え、混合物を80℃で3時間加熱した。3時間のコースの間、固体は混合物から単離された。次いで、懸濁液を58℃に冷却し、固体を集め、100mlのエタノールで洗浄し、40℃で減圧乾燥し、5gの3’(t−ブチル−ジフェニルシリル)−L−ネオプテリンを得た。3’(t−ブチル−ジフェニルシリル)−L−ネオプテリンの他の5gの画分は、室温で24時間残した後、ろ過から得られた。
50mlのアセトン−ジメチルアセタール中の10gの3’(t−ブチル−ジフェニルシリル)−L−ネオプテリン(実施例3に従って調製)を含む反応フラスコに、3.8gのパラ−トルエンスルホン酸を加えることにより、第二級ヒドロキシル基の保護を行い、1’2’−イソプロピリデン−3’O−(t−ブチル−ジフェニルシリル)−L−ネオプテリンを調製した。反応混合物を、室温で14時間撹拌した。生じた固体を集め、30mlのアセトン−ジメチルアセタールで洗浄し、35℃で減圧乾燥し、6.5gの1’2’−イソプロピリデン−3’(t−ブチル−ジフェニルシリル)−L−ネオプテリンを得た。
L−ネオプテリンの第一級ヒドロキシルのチオエーテルへの変換を行い、6−((1R,2R)−1,2−ジヒドロキシ−3−フェニルチオプロピル)−2−〔(メチルエチル)アミノ〕−3−ヒドロプテリジン−4−オン(図4において“15”と表示された化合物)を調製した。50グラムの6−((2S,1R)−1,2,3−トリヒドロキシプロピル)−2−〔(1Z)−1−アザ−2−(ジメチルアミノ)ビニル〕−3−ヒドロキシプテリジン−4−オン(DMA−ネオプテリン、図2において“6”と表示された化合物)を含むフラスコに、400mlのジメチルアミノアセテートをフラスコに加えた。この撹拌混合物に、1モル当量のジフェニルジスルフィド及びトリブチルホスフィンをフラスコに加えた。室温で、DMA−ネオプテリンがジメチルアミノアセテートに低い溶解性を示すことがわかった(約3.5mg/ml)。ジメチルアミノアセテート中で、チオエーテル生成物がそれ以上に溶解できると信じられている。反応混合物を、室温で4時間撹拌した。9グラムのチオエーテル生成物が単離された。
実施例5で調製されたチオエーテル生成物を、下記手段に従ってラネーニッケルで還元した。チオエーテル(9グラム、22ミリモル)をフラスコに加え、フラスコを360mlのエタノールで満たした。エタノール中のチオエーテルの撹拌混合物に、エタノール中の90グラムのラネーニッケルを加え、反応混合物を、圧力5バールの水素の雰囲気下に置いた。反応混合物を17時間撹拌した。
Claims (24)
- 鏡像異性体的に富化されたテトラヒドロビオプテリン(BH4)又はその塩をネオプテリンから形成する方法であって:
(a)ネオプテリンの第一級ヒドロキシル基をシリル保護基と反応させ、シリルエーテルを形成する工程;
(b)ネオプテリンの少なくとも1つの第二級ヒドロキシル基を、少なくとも1つの第二級ヒドロキシル保護基で保護する工程;
(c)工程(a)で形成されたシリルエーテルを、ハロゲン、スルホネート及びチオエーテルからなる群から選択される代用基に変換する工程;
(d)工程(c)の代用基を水素に還元する工程;及び
(e)工程(b)で追加した第二級ヒドロキシル保護基を除去する工程、
を含んで成る方法。 - 前記工程(a)を実施する前に、ネオプテリンのC−2位にある第一級アミン基を2−アミノ保護基で保護し、そして工程(a)を実施した後に2−アミノ保護基を除去する工程を更に含んで成る、請求項1に記載の方法。
- 前記2−アミノ保護基が、ジアルキルホルムアミドジアルキルアセタール基又はピバロイル基を含んで成る、請求項2に記載の方法。
- 前記ジアルキルホルムアミドジアルキルアセタール基が、N,N−ジメチルホルムアミドジエチルアセタール基及びN,N−ジメチルホルムアミドジエメルアセタール基からなる群から選択される、請求項3に記載の方法。
- 工程(a)の前記シリル保護基が、直鎖アルキル置換シリル基、分岐鎖アルキル置換シリル基及びアリール置換シリル基からなる群から選択される、請求項1に記載の方法。
- 前記シリル保護基が、t−ブチルジメチルシリル基又はt−ブチルジフェニルシリル基を含んで成る、請求項5に記載の方法。
- 前記少なくとも1つの第二級ヒドロキシル保護基が、アセタール又はケタールを含んで成る、請求項1に記載の方法。
- 前記ケタールが、イソプロピリデンケタールを含んで成る、請求項7に記載の方法。
- 前記代用基が、ハロゲンを含んで成り、工程(c)の変換がシリルエーテルとトリフェニルホスフィンハロゲンを反応させることを含んで成る、請求項1に記載の方法。
- 前記代用基がスルホネートを含んで成り、工程(c)の変換が前記シリルエーテルを除去し第一級ヒドロキシル基を形成させ、そして生じた第一級ヒドロキシル基をスルホン化すること、を含んで成る、請求項1に記載の方法。
- 前記代用基がチオエーテルを含んで成り、工程(c)の変換が前記シリルエーテルと(1)トリフェニルホスフィン、(2)アゾジカルボン酸ジアルキル及び(3)チオールの混合物とを反応させること、を含んで成る、請求項1に記載の方法。
- 工程(d)の還元が、工程(c)の代用基と、(1)ラネーニッケル試薬及び水素又は(2)水素化ホウ素ナトリウムを含んで成る還元剤とを反応させること、を含んで成る、請求項1に記載の方法。
- (f)工程(e)の生成物のエリトロ選択還元を実施してBH4又はその塩を形成する工程、
を更に含んで成る、請求項1に記載の方法。 - (g)前記BH4塩を結晶化すること、
を更に含んで成る、請求項13に記載の方法。 - 以下の式の化合物
R2はジエチルイソプロピルシリル、ジメチルイソプロピルシリル、ジメチルフェニルシリル、ジフェニルイソプロポキシシリル、ジフェニル−t−ブトキシシリル、ジ−t−ブチルメチルシリル、ジ−t−ブチルシリレン、メチルジイソプロピルシリル、メチルジフェニルシリル、t−ブチルメトキシフェニルシリル、t−ブチルジメチルシリル、テキシルジメチルシリル、トリエチルシリル、1,1,3,3−テトライソプロピルジシロキサン、トリイソプロピルシリル、トリメチルシリル、トリメチルシリルオキシカボミル(cabomyl)及びt−ブチルジフェニルシリルからなる群から選択されるシリル基であり;
R3はNH2、2,2−ジメチルプロパンアミド、1つの直鎖アルキル置換アミノ基、1つの分岐鎖アルキル置換アミノ基、2つの直鎖アルキル置換アミノ基、2つの分岐鎖アルキル置換アミノ基及び一置換アミノ基、からなる群から選択され;
R4は、隣接する2つの酸素原子と一緒に、メチレンアセタール、エチリデンアセタール、t−ブチルメチリデンケタール、1−t−ブチルエチリデンケタール、1−フェニルエチリデンケタール、1−(4−メトキシフェニル)エチリデンアセタール、2,2,2−トリクロロエチリデンアセタール、アクロレインアセタール、シクロペンチリデンケタール、シクロヘキシリデンケタール、シクロヘプチリデンケタール、ベンジリデンアセタール、p−メトキシベンジリデンアセタール、2,4−ジメトキシベンジリデンケタール、3,4−ジメトキシベンジリデンアセタール、2−ニトロベンジリデンアセタール、4−ニトロベンジリデンアセタール、メシチレンアセタール、1−ナフトアルデヒドアセタール、ベンゾフェノンケタール、及びイソプロピリデンケタールからなる群から選択される置換アセタール又はケタール基を形成し;
R5はハロゲンであり;
R6は、直鎖アルキル置換スルホネート、分岐鎖アルキル置換スルホネート、及びアリール置換スルホネートからなる群から選択され;そして
R7は、直鎖アルキル基、分岐鎖アルキル基、及びアリール基からなる群から選択される)。 - R6がトシル基を含んで成る、請求項15に記載の化合物。
- 鏡像異性体的に富化されたテトラヒドロビオプテリン(BH4)又はその塩をネオプテリンから形成するのに有用な方法であって:
(a)ネオプテリンのC−2位の第一級アミン基を、アミノ保護基で保護する工程;
(b)ネオプテリンの第一級ヒドロキシル基をチオエーテルに変換する工程;及び
(c)工程(b)のチオエーテルを水素に還元する工程、
を含んで成る方法。 - 前記工程(c)が、同時に、第一級アミノ保護基を除去して、エリトロ選択的還元を実施することで、BH4又はその塩を形成すること、を更に含んで成る、請求項17に記載の方法。
- 前記チオエーテルの還元が、ラネーニッケルと水素を用いることを含んで成る、請求項17に記載の方法。
- 工程(c)の後に第一級アミン保護基の除去工程を更に含んで成る、請求項17に記載の方法。
- 前記除去が、塩化亜鉛を用いてエタノール溶剤中で反応させることを含んで成る、請求項20に記載の方法。
- エリトロ選択的還元工程を更に含んで成り、BH4又はその塩を生成させる、請求項20に記載の方法。
- 前記エリトロ選択的還元が、(1)アルカリ性媒体中で水素化ホウ素ナトリウムを用いるか、又は(2)水素及び触媒量の二酸化白金を用いることを含んで成る、請求項22に記載の方法。
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PCT/US2004/038313 WO2005049614A2 (en) | 2003-11-17 | 2004-11-17 | Processes for preparing tetrahydrobiopterin, and analogs of tetrahydrobiopterin |
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BRPI0416566A (pt) | 2003-11-17 | 2007-01-23 | Biomarin Pharm Inc | tratamento de fenilcetonúrias com bh4 |
WO2006055511A2 (en) | 2004-11-17 | 2006-05-26 | Biomarin Pharmaceutical Inc. | Stable tablet formulation of tetrahydrobiopterin |
WO2008089008A2 (en) * | 2007-01-12 | 2008-07-24 | Biomarin Pharmaceutical Inc. | Tetrahydrobiopterin prodrugs |
EP4029519A1 (en) | 2007-04-11 | 2022-07-20 | BioMarin Pharmaceutical Inc. | Tetrahydrobiopterin for treating conditions associated with elevated phenylalanine levels |
ES2524026T3 (es) | 2008-01-03 | 2014-12-03 | Biomarin Pharmaceutical Inc. | Análogo de pterina para tratar una afección que responde a BH4 |
AR070109A1 (es) | 2008-01-07 | 2010-03-17 | Biomarin Pharm Inc | Metodo para sintetizar tetrahidobiopterina |
US9216178B2 (en) | 2011-11-02 | 2015-12-22 | Biomarin Pharmaceutical Inc. | Dry blend formulation of tetrahydrobiopterin |
CN102633799B (zh) * | 2012-04-10 | 2014-06-25 | 凯莱英医药集团(天津)股份有限公司 | 一种从消旋体中间体拆分路线合成二盐酸沙丙蝶呤的方法 |
JP6084967B2 (ja) * | 2012-05-07 | 2017-02-22 | 白鳥製薬株式会社 | セピアプテリン及びテトラヒドロラクトイルプテリンの製造法 |
WO2016189542A1 (en) | 2015-05-28 | 2016-12-01 | Natco Pharma Ltd | Novel process for the preparation of sapropterin dihydrochloride and its key intermediate, l-biopterin |
SG11201811603WA (en) | 2016-07-26 | 2019-02-27 | Biomarin Pharm Inc | Novel adeno-associated virus capsid proteins |
CA3043499A1 (en) | 2016-11-29 | 2018-06-07 | Censa Pharmaceuticals Inc. | Polymorphic form of sepiapterin |
US11072614B2 (en) | 2016-11-29 | 2021-07-27 | Ptc Therapeutics Mp, Inc. | Polymorphs of sepiapterin and salts thereof |
JP2020532535A (ja) | 2017-09-01 | 2020-11-12 | ピーティーシー セラピューティクス エムピー,インコーポレイテッド | セピアプテリンを含む医薬組成物及びその使用 |
US11739345B2 (en) | 2018-05-09 | 2023-08-29 | Biomarin Pharmaceutical Inc. | Methods of treating phenylketonuria |
TW202005978A (zh) | 2018-05-14 | 2020-02-01 | 美商拜奧馬林製藥公司 | 新穎肝靶向腺相關病毒載體 |
AU2019277382A1 (en) | 2018-05-30 | 2021-01-21 | Ptc Therapeutics Mp, Inc. | Methods for increasing sepiapterin plasma exposure |
AR122409A1 (es) | 2020-04-03 | 2022-09-07 | Biomarin Pharm Inc | Tratamiento de la fenilcetonuria con aav y formulaciones terapéuticas |
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